ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1288G>A (p.Glu430Lys)

gnomAD frequency: 0.00012  dbSNP: rs375433002
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000631090 SCV001371700 uncertain significance Glycogen storage disease, type II 2023-04-06 reviewed by expert panel curation The NM_000152.5:c.1288G>A (p.Glu430Lys) variant in GAA has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00043 (10/23086 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.577 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. SpliceAI predicts no impact on splicing. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of functional studies are not available. However, there is a ClinVar entry for this variant (Variation ID: 501777). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 6, 2023)
Eurofins Ntd Llc (ga) RCV000597568 SCV000708268 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000631090 SCV000752083 uncertain significance Glycogen storage disease, type II 2022-08-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 430 of the GAA protein (p.Glu430Lys). This variant is present in population databases (rs375433002, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 501777). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000631090 SCV002816262 uncertain significance Glycogen storage disease, type II 2021-09-07 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000597568 SCV003810581 uncertain significance not provided 2022-05-05 criteria provided, single submitter clinical testing
Natera, Inc. RCV000631090 SCV002092007 uncertain significance Glycogen storage disease, type II 2021-01-06 no assertion criteria provided clinical testing

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